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LESSONS FROM COVID-19

Advancing Development of Universal

Stacey Knobler, Cassidy Howell, Marissa Malchione, Ben McCormick, Alison Mack December 7th, 2020

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TABLE OF CONTENTS

Table of Contents ...... 2

Introduction ...... 3

Reckoning with COVID-19 ...... 3

Disarming a Looming ...... 4

Learning from the COVID-19 experience ...... 5

Emerging S&T Builds on a Strong Foundation of Fundamental Research ...... 6

Collaboration and Information Sharing ...... 7

Funding and Investment ...... 10

Product-focused, End-to-end Development ...... 12

Streamlining Regulatory Pathways ...... 13

Ensuring Global Access ...... 15

Summary and Conclusion ...... 16

References ...... 17

About Sabin ...... 23

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INTRODUCTION For the past century, the modern pandemic experience was defined in large part by the global phenomenon of H1N1 influenza in 1918-20 (1)—a model now rapidly being revised, as COVID-19 spreads unchecked across an interconnected world. Despite decades of warnings of the threat posed by emerging infectious diseases (2– 4), humanity has proven tragically underprepared to defend itself against a novel pathogen. As we suffer the consequences of this collective failure of unheeded foresight and imagination, we must seek knowledge that will us to better face future pandemic threats—including the certain emergence of a novel influenza (5).

RECKONING WITH COVID-19 Identifying and assessing the wide-ranging impacts of COVID-19 on diverse individuals, communities, populations, economic sectors, and systems will require years of scrutiny. Currently available measures of disease burden and socioeconomic disruption paint a grim picture that darkens with each day of uncontrolled disease transmission. At the time of this writing, approximately one year since the emergence of SARS-CoV-2 (the virus that causes COVID-19), the World Health Organization (WHO) reports more than 65 million confirmed cases of COVID-19, and 1.5 million deaths (6). Within the United States, the Centers for Disease Control and Prevention (CDC) reports more than 14 million cases and over 280,000 deaths since January 21, 2020 (7), and forecasts that nearly 330,000 COVID-19 deaths could be reported by the end of the calendar year (8). These numbers vastly underestimate the health burden associated with COVID-19, as indicated by significant excess deaths during 2020 as compared with recent years (9). A combination of an overloaded health systems, along with fear of exposure and barriers to care posed by measures, appear to have reduced uptake of preventive medical care, childhood (10,11), and diagnosis and treatment of life-threatening conditions, including symptoms of heart attack and stroke (12). The pandemic has also sparked a global mental health crisis (13), as rising rates of anxiety, depression, and suicidal ideation were met with disrupted mental health services (14,15). In October 2020, the International Monetary Fund (IMF) estimated that lost productivity due to COVID-19 would cost the world $28 trillion through the end of 2025, of which $11 trillion would be lost by the end of 2021 (16). Using different methods, cumulative financial costs of the pandemic in the United States alone have been estimated at more than $16 trillion, or about half the nation’s annual gross domestic product (17). However, as Nobel Prize-winning economist Joseph Stiglitz points out, “COVID-19 has not been an equal opportunity virus: it goes after people in poor health and those whose daily lives expose them to greater contact with others. And this means it goes disproportionately after the poor, especially in poor countries and in advanced economies like the United States where access to health care is not guaranteed (18).” Predictably, inequalities exposed and exacerbated by the coronavirus pandemic have sparked social unrest (19). and behavioral responses to COVID-19 have varied widely across the globe and over the course of the pandemic, from the level of national law (20) down to individual perceptions and actions (21,22). “Building the plane while flying it” has become the cliché du jour, as society responds to rapidly evolving epidemiological knowledge of SARS-CoV-2 and its myriad social implications. The rapid and collaborative response by the scientific and medical communities to COVID-19 will surely rank among the most important and effective, and one that is potentially transformative (23–26). Academia, companies of all sizes, philanthropies, governments, and multilateral organizations have joined forces in cooperative enterprises unprecedented in both number and design to confront the pandemic threat (27–32). Information and results—including negative ones—are being shared beyond constraints previously imposed by intellectual property rights and competition for academic or market advancement. Pre-print servers medRxiv and bioRxiv have been flooded with coronavirus research outputs, albeit of varied quality(33), awaiting peer- review; scientific journals are being pressed to provide free access to their contents (34).

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The phenomenal scientific response to COVID-19 has already produced a wealth of advancements, including diagnostic methodologies, treatment protocols, therapeutics such as monoclonal , and hundreds of vaccine candidates representing a range of longstanding and novel technologies. Promising vaccines, developed and tested in record time, not only inspire hope that this pandemic can be extinguished, but that productive changes forced upon the vaccine research and development ecosystem by COVID-19 can be sustained and applied to developing vaccines to avert future —and in particular, to tackle the persistent health burden and certain pandemic threat of influenza.

DISARMING A LOOMING PANDEMIC Devastating as the COVID-19 pandemic has been, and is projected to be, its death toll—now estimated at 1.5 million(6)—is dwarfed by that of the 1918-1920 influenza pandemic, which killed an estimated 50 million people (35). Subsequent flu pandemics in 1957,1968, 1977, and 2009 took between 2 and 4.5 million lives, combined. An influenza virus as deadly as the 1918 strain, which reduced the world’s population by about 3 percent, would today cause more than 230 million deaths. “A worldwide influenza pandemic is literally the worst-case scenario in — yet far from an unthinkable occurrence,” warned epidemiologist Michael Osterholm in 2018. “Unless we make changes, the question is not if but when it will come (36).”

Meanwhile, every year, seasonal flu costs 300,000 to 600,000 lives and millions of dollars in lost As the COVID-19 experience demonstrates, productivity—despite the existence of influenza time is of the essence in the early stages of a vaccines that, while lifesaving, are far from ideal. To pandemic. Even a heroic vaccine keep up with fast-mutating influenza , flu development effort takes months to bear vaccines are reformulated every year, and are rarely more than 50 percent effective at preventing fruit, while lives and livelihoods are . This is perhaps not surprising, since the destroyed. annual vaccine is developed through a laborious process of tracking and predicting which viral strains will prevail. Moreover, more than 90 percent of flu vaccine is produced by egg-based manufacturing, which takes months to complete—during which time a novel influenza strain could easily spread across the globe, killing millions of people (37). Comprehensive protection from influenza necessitates a transition from reactive annual development to universal influenza vaccines (UIVs): vaccines that provide lifelong or multi-year protection against a broad spectrum of influenza strains (38). Such vaccines would reduce barriers to access in many low- and middle-income countries that currently lack influenza programs due to the expense and logistical difficulties associated with annual targeting most of the population. Most importantly, provision of UIVs before the emergence a novel influenza virus would provide the preemptive protection needed to prevent a pandemic before it starts. As the COVID-19 experience demonstrates, time is of the essence in the early stages of a pandemic. Even a heroic vaccine development effort takes months to bear fruit, while lives and livelihoods are destroyed. Accelerating next-generation influenza vaccine research and development in pursuit of a UIV is the mission of the Influenzer Initiative at the Sabin Vaccine Institute. But, like the rest of the world, COVID-19 swiftly altered our efforts and our perspective. Recognizing that the vaccine R&D ecosystem was undergoing rapid and wide- ranging change in response to the pandemic, we committed to examine this transformation and its influence on the future of UIV development and the development of other vaccines against pathogens with pandemic potential.

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LEARNING FROM THE COVID-19 EXPERIENCE The diverse, multi-sectoral community now responding to COVID-19—which includes many participants in influenza R&D—is gaining knowledge, tools and experience that that can be applied to advance progress toward a UIV. To learn how to sustain and harness this extraordinary momentum, we embarked on a multi- pronged investigation with three main goals:

• Capture novel and optimized approaches to vaccine development employed in this crisis; • Identify factors that enable progress toward successful vaccine development, as well as persistent barriers to progress; and, • Assess the potential impact of COVID-era advances on prospects for a UIV To shape our inquiry and provide background and context for our findings, we are engaged in ongoing landscaping and analysis of relevant scientific literature, policy research resources, and public reporting. In October 2020, we anonymously surveyed a broad spectrum of professionals—in the life sciences, vaccinology, pandemic preparedness, vaccine regulation, policy, and funding—to capture quantitative and qualitative information. Survey questions explored three areas: vaccine R&D; drivers and incentives for COVID-19 vaccine R&D; and novel and technology (S&T). We are also conducting interviews with key stakeholders in vaccine development to further examine the intersection of the R&D response to COVID-19, the threat of pandemic influenza, and the pursuit of a UIV. Here we share our findings to date, including results from our survey, which received 235 responses from a diverse field of organizations (see Figure 1). Responses came from 46 countries, and eighty-two percent of the respondents identified as belonging to organizations currently involved in responding to COVID-19 (see Figure 2).

Figure 1.Sectoral distribution of survey respondents.

Figure 2. Geographic distribution of survey respondents. SABIN VACCINE INSTITUTE 5

Survey responses revealed significant trends in the following areas, each of which we will explore in this paper: Science, not cynicism, rules • The role of fundamental research and emerging S&T in the day accelerating vaccine development • New collaborative and data-sharing efforts No less remarkable—but far less appreciated— than the swift development of several promising • Funding and investment in vaccine R&D COVID-19 vaccines is the wealth of emerging • Product-focused vaccine research with end-to-end support science and technologies that made this spanning research, discovery, development, manufacturing phenomenon possible. Developed over years of painstaking research and refined through and distribution application to multiple vaccine targets, nucleic • Streamlined regulatory pathways acid- and viral vector-based platforms had been groomed for “plug and play” creation of vaccines • New production methods and distributed manufacturing to against emerging pathogens. increase speed and equity of vaccine distribution Among these is a platform recognized as a promising basis for UIV development (75). The non-replicating chimpanzee adenoviral vector vaccine (ChAdOx1) developed by Sarah Gilbert Emerging S&T Builds on a Strong Foundation of and colleagues at Oxford University, upon which they quickly built the COVID-19 vaccine produced Fundamental Research by AstraZeneca, was previously used to create a vaccine against two conserved influenza The rapid research response to COVID-19 mounted by the vaccine that produced long-lasting cellular in a R&D ecosystem drew on decades of robust fundamental research in Phase 1 trial (76,77). ChAdOx1 is also the basis for a vaccine recently demonstrated immunology, rapid genetic sequencing capabilities to quickly to be safe and immunogenic in a Phase 1 trial establish etiology and unravel pathogenesis, and on the of (78). , particularly SARS-CoV and MERS-CoV. This all- Even closer, Gilbert and her team had developed hands-on-deck effort also made strategic use of emerging S&T: for a robust vaccine against another coronavirus, example, nucleic acid- and viral vector-based platforms never before MERS (79,80). Springing into action with the SARS-CoV-2 sequence, they swiftly engineered a used in a vaccine brought to market. vaccine candidate for COVID-19; it advanced to clinical trials in April 2020, supported initially by a Before COVID-19 struck, such platforms were being explored for use $2.7 million grant from the UK government, and in other vaccines, including next-generation influenza vaccines (39) eventually in partnership with AstraZeneca (81). Interim results of Phase II/III trials, announced in [see Science, not cynicism, rules the day ]. Together, they are late November 2020—though complicated by employed in about 40 percent of vaccine candidates currently in methodological issues related to the conduct of clinical trials, as shown in Figure 3, and in 6 of 10 leading COVID-19 those trials—confirm the vaccine’s efficacy (80,82). Ongoing Phase III trials conducted in vaccine candidates, as shown in Table 1 (40). These include mRNA several countries are anticipated to enroll up to vaccines from Moderna and Pfizer, whose recent announcements of 60,000 volunteers. better-than-expected preliminary Phase III results made headlines. If The power of fundamental research and discovery such ground-breaking vaccines prove safe and effective against to solve the world’s complex challenges is no SARS-CoV-2, knowledge and momentum gained in their better demonstrated than in the laudable work of the many researchers seeking to counter the development could propel progress toward a UIV. assault from COVID-19. Their inspiring achievements provide a roadmap for avoiding such calamity in the future—and our first destination should be universal influenza vaccines available before the next pandemic strikes.

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Table 1. Leading COVID-19 Vaccine Candidates(40)

Leading Candidates Vaccine Categories Clinical Phase

BioNTech/Fosun/Pfizer RNA Regulatory Review

Moderna RNA Regulatory Review

University of Oxford/AstraZeneca Non-Replicating Viral Vector III

Sinovac/Instituto Butantan Inactivated Virus Wuhan Institute/Sinopharm Inactivated Virus III Beijing Institute/Sinopharm Inactivated Virus III Gamaleya Research Institute Non-Replicating Viral Vector III CanSino Biologics Non-Replicating Viral Vector III Janssen Pharma Non-Replicating Viral Vector III Novavax Subunit III

Figure 3. The regulatory status of 237 COVID-19 vaccines, organized by technology platform, as of December 2, 2020. Two COVID-19 vaccines are in regulatory review and seven have entered phase III trials. Data from the Milken Institute (40). Collaboration and Information Sharing The title of a New York Times story from April 2020 heralds a remarkable cultural shift that may outlast the pandemic: Covid-19 Changed How the World Does Science, Together (24). Six months later, respondents to our survey ranked collaborative work and information-sharing as top accelerating factors in COVID-19 development that should be carried forward in order to advance other pandemic vaccines (see Figure 4).

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Figure 4. Survey responses to the question, “Which elements currently being employed to accelerate COVID-19 vaccine development should carry forward to accelerate development of other pandemic vaccines?” The top three responses related to collaborative engagement: formal collaborations; consortia for research and development; and IP- and data-sharing and rapid publication.

Interestingly, when asked a similar question specific to future UIV development, respondents ranked factors related to scientific discovery and knowledge above those related to collaboration, reflecting significant research challenges yet to be overcome to create a UIV (see Figure 5).

Figure 5. Survey responses to the question shown above, among choices shown on the horizontal axis. Here, top responses reflect the primacy of gaining and applying scientific knowledge in pursuit of a UIV.

As one survey respondent noted, “new partnership between academic institutions, public sectors and industries, along with the sharing of basic research, freely accelerated the vaccine pace against COVID-19.”

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Partnerships between academia and pharma and public-private partnerships have flourished [see Novel partnerships pick up the tab, pick up the pace]. Novel partnerships pick up the Researchers and experts from outside the vaccine R&D tab, pick up the pace ecosystem are also lending their expertise to the COVID-19 response. Thirty-seven percent of survey respondents reported Not surprisingly, the three COVID-19 vaccines farthest along the development pipeline received that they were collaborating with representatives of fields not unprecedented levels of funding (40). However, they traditionally associated with vaccine development, including also benefitted from new funding structures: cross- sectoral and public-private partnerships involving computer science, computational biology and bioinformatics, academia, companies of all sizes, and direct , and physics. Forty-nine percent of organizations governmental engagement. funding vaccine R&D prior to COVID-19 reported supporting new The previously described partnership between grantees or partners at the time of the survey. The Academic and Oxford University and AstraZeneca marked a new Biotech/Pharma sectors accounted for the most reported new level of commitment on the part of industry to manufacture the vaccine, later named AZD1222, partnerships as seen in Figure 6. Such collaborations, which at while clinical trials were still underway. A multi- partner consortium is enabling clinical development and manufacturing of the vaccine in India, as discussed below.

Collaboration between NIH researchers and Moderna,a clinical-stage biotechnology company, created the COVID-19 vaccine candidate mRNA- 1273 (83); its first clinical batch was funded by CEPI. An additional partner, Lonza, will undertake larger- scale manufacturing of the vaccine, funded in part by BARDA, which also funds late-stage clinical development for this vaccine candidate.

Pharma giant Pfizer and German biotechnology company BioNTech collaborated to produce the mRNA vaccine BNT162b2, the first COVID-19 vaccine to receive an emergency use authorization Figure 6. Sectors reporting new partners. (in the UK) (84). BioNTech received funding from the German government to accelerate manufacturing least temporarily abandon traditional disciplinary and sectoral and development in that country (85); Pfizer funded siloes, could inform future efforts to develop pandemic vaccines, the vaccine’s global development through Phase III clinical trials, and it will deliver the approved vaccine. including a UIV. However, Pfizer’s investment risk was significantly reduced by advance purchase commitments for the Information—grease to the wheels of collaboration—flowed with vaccine through BARDA (86).

unaccustomed ease among R&D partners responding to COVID- Novel partnerships are also supporting ramped-up 19, and across disciplines, sectors, and borders. Because few vaccine development aimed at providing COVID-19 institutions explicitly reward open and early data sharing and the vaccines for low and middle-income countries (LMICs): tangible results it may produce, sustaining this pandemic-era cultural shift will require systemic change. For example, criteria • A public-private partnership between Bharat Biotech and two Indian government research for professional advancement in academic research, which institutions is developing , currently emphasize formal publications and funding awards, tend to undergoing phase III trials (87). Bharat has also discourage collaborative engagement. Incentivizing data sharing licensed a novel adenovirus-based, single-dose intranasal COVID-19 vaccine from Washington for critical problem-solving, whether or not it results in publication, University School of Medicine (St. Louis). could enhance international and inter-sectoral scientific cooperation and, as one survey respondent wrote, move • The Serum Institute of India (SII) and the Indian Council of Medical Research have collaborated academic R&D “away from using funding to ‘print scientific in the clinical development of the AstraZeneca papers’ onto encouraging finding solutions to real problems.” COVID-19 vaccine candidate (known as COVISHIELD in India), and another by Novavax Seeking to identify ways to facilitate ongoing sharing of data and (88). The SII is expected to manufacture several different COVID-19 vaccines, for which they information, which in turn could sustain new partnership models have received $150 million in support from The to advance vaccine R&D, we asked survey respondents, “what Bill and Melinda Gates Foundation and Gavi professional advancement could institutions adopt to (89,90). privilege data sharing, whether or not it results of publication?” Several responses advocated for the establishment of formal SABIN VACCINE INSTITUTE 9

performance criteria related to collaboration and data-sharing, and one endorsed dedicated intellectual property (IP) support to facilitate the legal sharing of proprietary data. Funding and Investment Multiple estimates of the economic costs of COVID-19 (16,17), calculated according to a variety of models, convey a single message: the staggering consequences of this pandemic, both acute and enduring—and far exceeding previous damage estimates for “” (41,42). Just the portion of pandemic-associated expense represented by G20 countries’ spending to support their faltering economies—an estimated $10 trillion by September 2020 (43)—dwarfs the $35 billion investment required to fully fund the medical response to COVID-19, as projected by the Access to COVID-19 Tools (ACT) Accelerator, a collaborative initiative of governments, scientists, businesses, civil society, and philanthropists and organizations (see Figure 7) (32,43).

Figure 7. Comparison of funds required for the global medical response to COVID-19 through the ACT-Accelerator with economic support unlocked by ten countries, as of September 10, 2020. Source: ACT Accelerator Investment Case & Plan (43).

The ACT-Accelerator, which supports the development and equitable distribution of tests, treatments and vaccines for COVID-19, is one among several important public-private partnerships formed in response to the pandemic (44) (See Figure 8). In an effort to ensure equal access to COVID-19 vaccines, the vaccine-specific effort of the ACT-Accelerator, COVAX, created a facility that partners countries of all income levels with vaccine manufacturers (29). A more limited initiative, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), coordinated by the Foundation for the National Institutes of Health, brings together US government agencies and departments—including the Biomedical Advanced Research and Development Authority (BARDA), CDC, U.S. Food and Drug Administration (FDA), Departments of Defense and Veterans Affairs, and the COVID-19 vaccine production and delivery effort, (45)—with the European Medicines Agency (EMA) and representatives from academia, philanthropic organizations, and numerous companies (46). The ACTIV vaccines working group aimed to streamline the vaccine regulatory process, including by supporting harmonized trials (47). Having completed its official charge in July 2020, the group continues to meet on an ad-hoc basis. In the future, one survey respondent noted, public-private partnerships like ACTIV could accelerate vaccine development by promoting “clinical trials with common endpoints, allowing comparisons across platforms and manufacturing at risk.”

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Return on investment in public- private vaccine development partnerships, relative to their potential to prevent catastrophic economic losses, is clearly vast— but could be even greater if directed toward pandemic prevention, rather than response. Thus, in addition to investigating how these partnerships have accelerated vaccine R&D, we want to learn how this momentum could be sustained to support the development of a UIV and other pandemic-preventive vaccines. Historically, the process of research and development for vaccines has been lengthy, expensive, and publicly funded (48,49). Only after a vaccine has proven safe, effective, and Figure 8. Examples of partnerships formed to develop COVID-19 vaccines. potentially profitable has a pharmaceutical company assumed the relatively low risk inherent in its manufacturing and distribution. The rapid development of vaccines against SARS-CoV-2 necessitated overriding these precedents, a transformation underwritten by governments (e.g. through programs such as Operation Warp Speed) (50), industry, non-governmental organizations including the Coalition for Epidemic Preparedness (CEPI) (51) and Gavi, the Vaccine Alliance (Gavi) (52), and philanthropy. Our survey results suggest that the COVID-19 crisis introduced new funding entities to the vaccine R&D ecosystem. As shown in Figure 9, the numbers of new funding sources representing international consortia, philanthropy, private investment, and venture capital topped previous totals in each of these categories. These trends suggest that among respondents, private sector supporters of catalytic, high-risk/high-reward ventures recognize investment potential in pandemic vaccines. This is an encouraging development, as it has long been recognized that new models are needed for financing pandemic vaccines (53). The previously described ACT-Accelerator aims to fill that and other critical needs through a purchasing collective—an approach that appeals to investors (e.g., governments, multilaterals, civil society, businesses, foundations) who expect to pay less to support a comprehensive response to COVID-19 than they would to endure an uncontrolled pandemic. It takes little imagination to extend that tradeoff to pandemic prevention, which in theory could result in far greater savings. As an alternative to these models, Lo and coauthors (2012) designed a financing strategy aimed at reducing the risk of investing in innovative research (53–55). They propose the creation of diversified portfolios of biomedical projects at all stages of development, valued at $5 to $30 billion. Financed by a combination of equity and securitized debt, these “megafunds” could provide much-needed investment capital for vaccine research and development. “With enough programs in a portfolio,” the authors argue, “the potential revenues become more certain, more easily valued by potential investors, and more attractive from a risk-reward perspective.” This framework was recently expanded specifically to address vaccines for emerging infectious diseases (EIDs), and in recognition of the high economic value of pandemic prevention in general, as compared with the financial returns available to commercial developers of individual vaccine assets. It features a capitated vaccine “subscription” model (similar to that pioneered by CEPI), supported by public and SABIN VACCINE INSTITUTE 11

philanthropic funding, to compensate industry partners focused on EID vaccines, as well as megafund-like large portfolios combining multiple EID vaccines (55). This dual strategy seeks to normalize investment risk while advancing efforts to ensure global and economic .

Figure 9. Funding sources reported by survey respondents conducting COVID-19 vaccine R&D.

Product-focused, End-to-end Development Scientific creativity, knowledge, and dedication were primary drivers of the COVID-19 vaccine development juggernaut that produced hundreds of diverse candidates. Responding to urgent need, coordinating efficiently, collaborating as never before, researchers and their partners across disciplines, sectors, and borders focused single-mindedly on finding the only viable exit from the pandemic: a safe, effective vaccine accessible to the entire world.

“Investigator initiated inquiries could prove Survey respondents acknowledged this demonstration of the power of product- more fruitful if complemented by a focused research, overwhelmingly agreeing structured research agenda framework that the same strategy could drive future designed to move research along toward a pandemic vaccine R&D built, like COVID-19 prioritized product-specific goal” vaccine candidates, on discoveries from investigator-initiated inquiry. As one respondent wrote, “Investigator initiated inquiries could prove more fruitful if complemented by a structured research agenda framework designed to move research along toward a prioritized product-specific goal.” Similarly, in explaining the ’s recent extension of support to goal-oriented as well as basic research, director Jeremy Farrar observed that “there are certain challenges, where you can’t just leave it to the idiosyncrasies of discovery…You have to have a greater sense of mission of where you’re trying to get to (56).” The record-setting pace of COVID-19 vaccine development also entails at-risk manufacturing of promising candidate vaccines, made possible by unprecedented funding strategies that have deployed resources commensurate with a global health and economic crisis. Rather than proceed through the typical linear development process, COVID-19 vaccine development is accelerated through the parallel execution of several key stages [see Multi-tasking vaccine development].

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The so-called end-to-end funding that ensured the swift passage of COVID-19 vaccines from discovery through distribution offers a promising framework for underwriting pandemic preparedness. In their August 2020 report (57) to the Global Preparedness Monitoring Board, Keusch and Lurie advocate the creation of “a global financing system that addresses the situation of the entire world having needs for diagnostics, therapeutics, vaccines and PPE….[by assuming] the financial risks for scale up, manufacturing at risk, purchasing commitments in support of a globally fair allocation system.” Responding to the COVID-19 crisis, the vaccine R&D ecosystem has demonstrated the immense power and efficiency afforded by product-focused research, supported end-to-end—from vaccine discovery through distribution—by a cross-sectoral partner network. Notably, these proven mechanisms could be even more effective if applied to pandemic prevention; for example, by accelerating UIV development.

Streamlining Regulatory Pathways Many national regulatory authorities have streamlined approval processes to expedite development of COVID- 19 vaccines, while international efforts to harmonize protocols have gained momentum and are expected to further accelerate vaccine development (66,67). Typical regulatory adaptations have included:

• Relaxation of pre-trial risk assessment requirements • Adapted trial protocols • Enabling conduct of some trial functions by sub-investigators at local sites • Use of electronic documentation methods • More flexible trial oversight, including remote monitoring • More flexible conduct of ethical reviews not involving patient safety (68) Additional changes in regulatory and review procedures aimed at accelerating COVID-19 vaccine development have included greater collaboration between researchers and regulators; the use of risk-benefit calculations to support regulatory decision making (69); the streamlining of Good Manufacturing Practices (GMP); the acceptance of Phase IV data collection and surrogate markers toward regulatory approval; and, the application of the FDA’s animal efficacy rule (in lieu of challenge trials, given the lack of therapeutics for COVID-19). Responding to concerns that the expedited regulatory pathway for COVID-19 vaccines could compromise their safety, NIH director sought to reassure the public. “While administrative steps are being streamlined to speed the process, safety and effectiveness measures are just as rigorous than ever,” he insisted (70). The pharmaceutical industry, stimulated by new levels of regulatory flexibility, is pressing for this to continue beyond the pandemic (71). Two-thirds of survey respondents apparently expect that to happen, agreeing that that “rapid and significant changes in vaccine R&D occurring in response to COVID-19 have the potential to permanently shift pandemic vaccine R&D.” In particular, as shown in Figure 10, they emphasized three features of the regulatory review and approval process associated with international harmonization and collaboration as having the potential to accelerate R&D for pandemic vaccines beyond COVID-19.

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Multi-tasking Vaccine Development: from serial to parallel processing The vaccine development cycle proceeds through a series of well-established stages. Moving through these stages typically occurs serially, and—for the tiny fraction of candidates that complete the process—often takes a decade or more, in large part because different stages involve different sectors (62). Academic researchers do most of the basic science and early development, usually with government support; industry (and sometimes government and/or academia) performs further applied research and clinical testing; government conducts regulatory review and approval; industry produces the vaccine and distributes it (sometimes with government assistance). Ongoing (Phase IV) studies of vaccines are generally conducted by the government, sometimes with assistance from academia or industry. The complexity, expense, and length of this process hinders innovation in vaccine R&D in general, and, in the specific case of vaccine candidates developed against SARS- and MERS-CoV, halted their development at the pre-clinical stage (63,64). By contrast, COVID-19 vaccine development proceeded seamlessly, as intersectoral collaboration minimized delays associated with handoffs. Collaboration—as well as at-risk funding for manufacturing—also enabled key development steps to occur in parallel, hastening the availability of successful vaccines.

Figure: Wellcome Trust (58); Data from Plotkin et al. 2017 (59), Prichep, E. (2020) (60), Lurie et al. 2020 (61)

Young, PR. Disease X ver1.0: COVID-19. Microbiol Aust. 2020 Jun 1; 41(2):109–12 (65)

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Figure 10. Survey responses to each version of the question shown favored three features: internationally harmonized approval processes for pandemic vaccines; harmonization and standardization of assay data with biological standards and the vaccine efficacy animal study; and, greater collaboration between researchers (academic and/or industry) and regulators on pre-clinical evaluation of novel technologies or discoveries.

“Regulatory approval of the novel technologies for COVID vaccines…will have provided additional scientific and technical experience and data that can be utilized for accelerated development of universal influenza vaccines that also utilize these technologies,” wrote one survey respondent. “Thus, the regulatory pathway for approval of influenza vaccines using these approaches should be clearer to industry and to investigators using these approaches.”

Ensuring Global Access Thanks to COVID-19, these epidemiological adages are familiar to many:

“No one is safe until everyone is safe.”

“Vaccines don’t stop disease; vaccination does.”

Acting on these truths, however, remains an aspiration—even in the midst of a pandemic (72). Public health advocates have long characterized vaccines as global public goods, to which fair and equitable access must be guaranteed. The previously described establishment of the COVAX facility represents a major step toward realizing this ideal; however, at the time of this writing, it remains underfunded (73). Moreover, as Keusch and Lurie (2020) observe, “realizing the goal that pandemic products are global public goods will likely require distributed manufacturing in multiple countries, so that no single country can seize

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products made within its borders for itself (57).” To improve global access to vaccines and other pandemic products, they recommend siting manufacturing capacity in multiple low- and middle-income countries. Such facilities, they note, should be aligned with the most promising platforms available, such as nucleic acid-based vaccines, requiring supporting investments in advanced manufacturing technology and the development of robust supply chains. Innovative, efficient vaccine production methods and technologies, employed in distributed manufacturing facilities, may increase access to pandemic vaccines, beginning with COVID-19. Novel partnerships—which could even involve bilateral agreements between competing companies—can ensure flexible, fungible vaccine manufacturing arrangements (74). Building on this foundation will significantly increase the impact of future pandemic vaccines, and the potential of a UIV to extinguish the imminent threat of pandemic influenza.

SUMMARY AND CONCLUSION COVID-19 offers both cautionary and encouraging lessons for the vaccine R&D ecosystem. The Influenzer Initiative recognizes that UIVs—vaccines providing protection from all influenza strains, including those with pandemic potential—offer more than pandemic preparedness: UIVs provide pandemic prevention. Our ongoing investigation of COVID-19 vaccine development aims to discover how the extraordinary momentum of pandemic response can be sustained and harnessed in pursuit of UIVs. The following findings, derived primarily from our October 2020 survey of key experts, summarize lessons learned to date:

• The advance of novel vaccine development platforms and technologies to produce safe and effective COVID-19 vaccines provides a glide path to accelerate next-generation influenza vaccine development. • Collaboration and open data sharing have encouraged innovation and progress toward a pandemic- ending vaccine, but explicit incentives will be required to sustain current levels of collaboration, beyond the pandemic response. • Pandemic vaccines are enormously cost-effective; a UIV capable of averting an inevitable pandemic disease would be an even greater bargain. Creative financing mechanisms can decrease investment risk necessary to promote innovation. • Product-focused R&D, backed by a network of partners providing end-to-end support, is immensely efficient in accelerating the development of innovative vaccines. • Regulatory pathways can be demonstrably streamlined through multiple mechanisms without compromising safety. • Improved manufacturing methods and technologies and distributed manufacturing strategies enable equitable access to vaccines and other global public health goods.

COVID-19 has shown us how devastating a pandemic can be, and also how rapidly the vaccine R&D ecosystem can respond to such a threat. These insights must inspire action now to protect the world from the influenza pandemic we know is coming.

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31. Collins FS, Stoffels P. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): An Unprecedented Partnership for Unprecedented Times. JAMA [Internet]. 2020 [cited 2020 Jun 15]; Available from: https://doi.org/10.1001/jama.2020.8920 32. The Access to COVID-19 Tools (ACT) Accelerator [Internet]. World Health Organization. 2020 [cited 2020 Dec 6]. Available from: https://www.who.int/initiatives/act-accelerator 33. Kwon D. How swamped preprint servers are blocking bad coronavirus research. Vol. 581, . NLM (Medline); 2020. p. 130–1. 34. Callaway E. Will the pandemic permanently alter scientific publishing? Nature. 2020 Jun 1;582(7811):167–8. 35. Saunders-Hastings PR, Krewski D, Young L. Reviewing the history of pandemic influenza: Understanding patterns of emergence and transmission. Pathogens [Internet]. 2016 Dec 6 [cited 2020 Dec 2];5(4). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198166/#!po=6.57895 36. Osterholm MT, Olshaker M. We’re Not Ready for a Flu Pandemic [Internet]. The New York Times. 2018 [cited 2020 Dec 2]. Available from: https://www.nytimes.com/2018/01/08/opinion/flu-pandemic-universal- vaccine.html 37. Bender E. Accelerating flu protection. Nature. 2019 Sep 19;573:S60–1. 38. Accelerating the Development of a Universal Influenza Vaccine. The Sabin-Aspen Vaccine Science & Policy Group. 2019. 39. Wei C-J, Crank MC, Shiver J, Graham BS, Mascola JR, Nabel GJ. Next-generation influenza vaccines: opportunities and challenges. Nat Rev Drug Discov [Internet]. 2020 Feb 14; Available from: http://www.ncbi.nlm.nih.gov/pubmed/32060419 40. COVID-19 Vaccine Tracker [Internet]. Milken Institute. 2020 [cited 2020 Dec 6]. Available from: https://www.covid-19vaccinetracker.org/ 41. Implementing the Global Health Security Agenda: Progress and Impact from U.S. Government Investments [Internet]. 2017 [cited 2020 Dec 2]. Available from: https://ghsagenda.org/wp- content/uploads/2020/06/ghsa-report-_feb-2018.pdf 42. Gostin LO, Mundaca-Shah CC, Kelley PW. Neglected dimensions of global security: The global health risk framework commission [Internet]. Vol. 315, JAMA - Journal of the American Medical Association. American Medical Association; 2016 [cited 2020 Dec 2]. p. 1451–2. Available from: https://jamanetwork.com/journals/jama/fullarticle/2505286 43. ACT Accelerator: Investment Case & Plan [Internet]. 2020 Sep [cited 2020 Dec 2]. Available from: https://www.who.int/publications/m/item/act-accelerator-plan-and-investment-opportunity-presentation 44. National Academies of Sciences E and M. Public Private Partnership Responses to COVID-19 and Future Pandemics [Internet]. Casola L, editor. Washington, D.C.: National Academies Press; 2020 [cited 2020 Dec 6]. Available from: https://www.nap.edu/catalog/25999 45. Fact Sheet: Explaining Operation Warp Speed [Internet]. Health & Services. 2020 [cited 2020 Dec 2]. Available from: https://www.hhs.gov/coronavirus/explaining-operation-warp-speed/index.html 46. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) [Internet]. National Institutes of Health (NIH). 2020 [cited 2020 Dec 6]. Available from: https://www.nih.gov/research-training/medical- research-initiatives/activ 47. Vaccines Working Group [Internet]. National Institute of Health. 2020 [cited 2020 Dec 2]. Available from: https://www.nih.gov/research-training/medical-research-initiatives/activ/vaccines-working-group 48. Stevens AJ, Jensen JJ, Wyller K, Kilgore PC, Chatterjee S, Rohrbaugh ML. The Role of Public-Sector Research in the Discovery of Drugs and Vaccines. N Engl J Med [Internet]. 2011 Feb 10 [cited 2020 Dec 2];364(6):535–41. Available from: https://www.nejm.org/doi/full/10.1056/nejmsa1008268

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49. Allen A. For Billion-Dollar COVID Vaccines, Basic Government-Funded Science Laid the Groundwork [Internet]. Scientific American. 2020 [cited 2020 Dec 2]. Available from: https://www.scientificamerican.com/article/for-billion-dollar-covid-vaccines-basic-government-funded- science-laid-the-groundwork/ 50. Schäferhoff M, McDade KK. Funding the development and manufacturing of COVID-19 vaccines: The need for global collective action [Internet]. [cited 2020 Dec 2]. Available from: https://www.brookings.edu/blog/future-development/2020/04/24/funding-the-development-and- manufacturing-of-covid-19-vaccines-the-need-for-global-collective-action/ 51. (No Title) [Internet]. CEPI. [cited 2020 Dec 2]. Available from: https://cepi.net/ 52. (No Title) [Internet]. GAVI. [cited 2020 Dec 2]. Available from: https://www.gavi.org/ 53. Avishai B. The Case for a Coronavirus Vaccine Bond [Internet]. 2020 [cited 2020 Dec 2]. Available from: https://www.newyorker.com/news/daily-comment/the-case-for-a-coronavirus-vaccine-bond 54. Fernandez JM, Stein RM, Lo AW. Commercializing biomedical research through securitization techniques. Vol. 30, Nature Biotechnology. 2012. p. 964–75. 55. Vu JT, Kaplan BK, Chaudhuri S, Mansoura MK, Lo AW. Financing Vaccines for Global Health Security. 2020 [cited 2020 Dec 3]; Available from: https://doi.org/10.1101/2020.03.20.20039966 56. Kupferschmidt K. In new strategy, Wellcome Trust takes on global health concerns. Sci [Internet]. 2020 Oct 23 [cited 2020 Dec 2];370(6515):392. Available from: https://science.sciencemag.org/content/370/6515/392.abstract 57. Keusch GT, Lurie N. The R&D Preparedness Ecosystem: Preparedness for Health Emergencies Report to the Global Preparedness Monitoring Board. 2020 Aug. 58. How can we develop a COVID-19 vaccine quickly? [Internet]. Wellcome Trust. 2020 [cited 2020 Dec 7]. Available from: https://wellcome.org/news/how-can-we-develop-covid-19-vaccine-quickly 59. Plotkin S, Robinson JM, Cunningham G, Iqbal R, Larsen S. The complexity and cost of vaccine manufacturing – An overview [Internet]. Vol. 35, Vaccine. Elsevier Ltd; 2017 [cited 2020 Dec 7]. p. 4064–71. Available from: /pmc/articles/PMC5518734/?report=abstract 60. Prichep E. Why a coronavirus vaccine takes over a year to produce – and why that is incredibly fast [Internet]. World Economic Forum. 2020 [cited 2020 Dec 7]. Available from: https://www.weforum.org/agenda/2020/04/why-a-coronavirus-vaccine-takes-over-a-year-to-produce- and-why-that-is-incredibly-fast/ 61. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med [Internet]. 2020 May 21 [cited 2020 Dec 2];382(21):1969–73. Available from: https://www.nejm.org/doi/full/10.1056/NEJMp2005630 62. Youngs H. The Science and Coordination Challenges in Influenza Vaccine Development [Internet]. 2020 [cited 2020 Dec 6]. Available from: https://www.influenzer.org/app/uploads/2020/03/The-Science-and- Coordination-Challenges-in-Influenza-Development.pdf 63. Padron-Regalado E. Vaccines for SARS-CoV-2: Lessons from Other Coronavirus Strains [Internet]. Vol. 9, Infectious Diseases and Therapy. Adis; 2020 [cited 2020 Dec 6]. p. 255–74. Available from: /pmc/articles/PMC7177048/?report=abstract 64. Hixenbaugh M. Scientists were close to a coronavirus vaccine years ago. Then the money dried up. [Internet]. NBC News. 2020 [cited 2020 Dec 6]. Available from: https://www.nbcnews.com/health/health- care/scientists-were-close-coronavirus-vaccine-years-ago-then-money-dried-n1150091 65. Young PR. Disease X ver1.0: COVID-19. Microbiol Aust [Internet]. 2020 Jun 1 [cited 2020 Dec 7];41(2):109–12. Available from: /pmc/articles/PMC7263844/?report=abstract 66. Edgar S. How streamlined regulatory processes may speed time to market for novel treatments

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[Internet]. Decision Resources Group . [cited 2020 Dec 2]. Available from: https://decisionresourcesgroup.com/downloads/streamlined-regulatory-processes-may-speed-time- market-novel-treatments/ 67. International regulators align positions on phase 3 COVID-19 vaccine trials [Internet]. 2020 [cited 2020 Dec 2]. Available from: https://www.ema.europa.eu/en/news/international-regulators-align-positions- phase-3-covid-19-vaccine-trials 68. Greater harmonisation of clinical trial regulations would help the fight against COVID-19 [Internet]. OECD. 2020 [cited 2020 Dec 2]. Available from: https://read.oecd-ilibrary.org/view/?ref=135_135577- 5gnj8yvrlg&title=Greater-harmonisation-of-clinical-trial-regulations-would-help-the-fight-against-COVID- 19 69. Arlegui H, Bollaerts K, Salvo F, Bauchau V, Nachbaur G, Bégaud B, et al. Benefit–Risk Assessment of Vaccines. Part I: A Systematic Review to Identify and Describe Studies About Quantitative Benefit–Risk Models Applied to Vaccines [Internet]. Vol. 43, Drug Safety. Adis; 2020 [cited 2020 Dec 6]. p. 1089–104. Available from: https://doi.org/10.1007/s40264-020-00984-7 70. Fourth large-scale COVID-19 begins in the United States [Internet]. National Institutes of Health. 2020 [cited 2020 Dec 2]. Available from: https://www.nih.gov/news-events/news-releases/fourth- large-scale-covid-19-vaccine-trial-begins-united-states 71. Florko N. The FDA got a lot more flexible during COVID- and pharma’s already pushing to make it permanent [Internet]. STAT. 20AD [cited 2020 Dec 2]. Available from: https://www.statnews.com/2020/07/23/fda-flexibility-pharma-push/ 72. Equitable COVID-19 vaccine distribution will lead to the biggest reduction in deaths | Gavi, the Vaccine Alliance [Internet]. GAVI. 2020 [cited 2020 Dec 2]. Available from: https://www.gavi.org/vaccineswork/equitable-covid-19-vaccine-distribution-will-lead-biggest-reduction- deaths 73. Over US$2 billion raised to support equitable access to COVID vaccines with additional US$ 5 billion needed in 2021 [Internet]. GAVI. 2020 [cited 2020 Dec 2]. Available from: https://www.gavi.org/news/media-room/over-us-2-billion-raised-support-equitable-access-covid- vaccines-additional-us-5 74. Agrawal G, Conway M, Sabow A, Tolub G. On pins and needles: Will COVID-19 vaccines ‘save the world’? [Internet]. McKinsey & Company. 2020 [cited 2020 Dec 6]. Available from: https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/on-pins-and- needles-will-covid-19-vaccines-save-the-world# 75. Sayedahmed EE, Elkashif A, Alhashimi M, Sambhara S, Mittal SK. Adenoviral Vector-Based Vaccine Platforms for Developing the Next Generation of Influenza Vaccines. Vaccines [Internet]. 2020 Oct 1 [cited 2020 Dec 6];8(4):574. Available from: https://www.mdpi.com/2076-393X/8/4/574 76. COVID Conversations: Sarah Gilbert on Oxford’s COVID-19 Vaccine [Internet]. . 2020 [cited 2020 Dec 6]. Available from: https://www.youtube.com/watch?v=MKNavonhXyk 77. Coughlan L, Sridhar S, Payne R, Edmans M, Milicic A, Venkatraman N, et al. Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults. EBioMedicine [Internet]. 2018 Mar 1 [cited 2020 Dec 6];29:146–54. Available from: http://creativecommons.org/licenses/by/4.0/ 78. Wilkie M, Satti I, Minhinnick A, Harris S, Riste M, Ramon RL, et al. A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime – MVA85A boost in healthy UK adults. Vaccine [Internet]. 2020 Jan 22 [cited 2020 Dec 6];38(4):779–89. Available from: https://pubmed.ncbi.nlm.nih.gov/31735500/ 79. Baker S, Lauerman J, Paton J. How Top Scientists are Racing to Beat the Coronavirus [Internet]. Bloomberg. 2020 [cited 2020 Dec 6]. Available from: https://www.bloomberg.com/news/features/2020- 03-30/coronavirus-the-scientists-hunting-for-treatments-vaccine SABIN VACCINE INSTITUTE 21

80. Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet [Internet]. 2020 Aug 15 [cited 2020 Dec 6];396(10249):467–78. Available from: https://doi.org/10.1016/ 81. AstraZeneca and Oxford University announce landmark agreement for COVID-19 vaccine [Internet]. AstraZeneca. 2020 [cited 2020 Dec 6]. Available from: https://www.astrazeneca.com/media- centre/press-releases/2020/astrazeneca-and-oxford-university-announce-landmark-agreement-for- covid-19-vaccine.html 82. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19 [Internet]. AstraZeneca. 2020 [cited 2020 Dec 6]. Available from: https://www.astrazeneca.com/media-centre/press- releases/2020/azd1222hlr.html 83. Moderna and Lonza Announce Worldwide Strategic Collaboration to Manufacture Moderna’s Vaccine (mRNA-1273) Against Novel Coronavirus [Internet]. Moderna, Inc. 2020 [cited 2020 Dec 6]. Available from: https://investors.modernatx.com/news-releases/news-release-details/moderna-and-lonza- announce-worldwide-strategic-collaboration 84. Pfizer and BioNTech Achieve First Authorization in the World for a Vaccine to Combat COVID-19 [Internet]. Pfizer. 2020 [cited 2020 Dec 6]. Available from: https://www.pfizer.com/news/press- release/press-release-detail/pfizer-and-biontech-achieve-first-authorization-world 85. Griffin R, Armstrong D. Pfizer Vaccine’s Funding Came From Berlin, Not Washington [Internet]. Bloomberg. 2020 [cited 2020 Dec 6]. Available from: https://www.bloomberg.com/news/articles/2020-11- 09/pfizer-vaccine-s-funding-came-from-berlin-not-washington 86. U.S. Government Engages Pfizer to Produce Millions of Doses of COVID-19 Vaccine [Internet]. HHS.gov. 2020 [cited 2020 Dec 6]. Available from: https://www.hhs.gov/about/news/2020/07/22/us- government-engages-pfizer-produce-millions-doses-covid-19-vaccine.html 87. Coronavirus: Bharat Biotech’s COVID-19 vaccine Covaxin enters phase-3 trials [Internet]. The Hindu. 2020 [cited 2020 Dec 6]. Available from: https://www.thehindu.com/news/national/coronavirus-bharat- biotechs-covid-19-vaccine-covaxin-enters-phase-3-trials/article33107393.ece 88. COVISHIELD Completes Enrolment of Phase III clinical trials under partnership of ICMR and Serum Institute of India [Internet]. Serum Institute of India PVT LTD. 2020 [cited 2020 Dec 6]. Available from: https://www.seruminstitute.com/news_sii_icmr_partnership.php 89. Fry E. ‘We’re racing against the clock’: The CEO of the Serum Institute of India on his company’s COVID-19 vaccine campaign [Internet]. Fortune. 2020 [cited 2020 Dec 6]. Available from: https://fortune.com/2020/09/21/coronavirus-serum-institute-of-india-ceo-covid-vaccine/ 90. India’s Serum Institute to get $150 million from Gates Foundation for COVID-19 vaccine [Internet]. Reuters. 2020 [cited 2020 Dec 6]. Available from: https://www.reuters.com/article/us-health-coronavirus- india-vaccine/indias-serum-institute-to-get-150-million-from-gates-foundation-for-covid-19-vaccine- idUSKCN2531B4

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ABOUT SABIN The Sabin Vaccine Institute is a leading advocate for expanding vaccine access and uptake globally, advancing vaccine research and development, and amplifying vaccine knowledge and innovation. Unlocking the potential of vaccines through partnership, Sabin has built a robust ecosystem of funders, innovators, implementers, practitioners, policy makers and public stakeholders to advance its vision of a future free from preventable diseases. As a non-profit with more than two decades of experience, Sabin is committed to finding solutions that last and extending the full benefits of vaccines to all people, regardless of who they are or where they live. At Sabin, we believe in the power of vaccines to change the world. For more information, visit sabin.org & influenzer.org and follow us on Twitter, @SabinVaccine & @TheInfluenzers.

A program of the Sabin Vaccine Institute 2175 K St, NW, Suite 400, Washington, DC 20037 +1 202 842 5025 sabin.org

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